1. Field of the Invention
The present invention relates to the use of ethylenediamine disuccinate and its pharmacologically compatible salt-forming ions and its protonated form for the preparation of a medicament having antiviral properties which also has an immunosuppressive effect.
2. The Prior Art
(S,S)-N,N'-ethylenediamine disuccinate is described in detail in a publication by Takaaki Nishikiori et al. (1984), The Journal of Antibiotics, Vol. 37, No. 4: 426-427. (S,S)-N,N'-ethylenediamine disuccinate can be recovered from actinomycetes and can also be prepared synthetically (J. A. Neal and N. J. Rose (1968), Inorg. Chem. Vol. 7; 2405-2412). It inhibits phospholipases C and D. If (S,S)-N,N'-ethylenediamine disuccinate is intraperitoneally administered to mice, their antibody production and DTH (delayed type hypersensitivity) reaction are suppressed. In vitro, blastogenesis of B cells and T cells is suppressed. However, this publication does not report an anti-microbial activity. The toxicity of the substance in mice is relatively low.
The cytomegaloviruses (CMV) constitute a group of related viruses which include the Herpes viruses (Lutz Schneider (1990) , Pharmazeutische Zeitung, Vol. 135, No. 27, 2396-2400). After an initial infection, the viruses remain in the body in a latent condition. Only when the immune system is weakened by a immunesuppression caused by medicaments or disease, the viruses become reactivated. The name of these viruses is derived from their causing histopathologically detectable giant cells with a marginal large nucleus and containing viruses as inclusion bodies.
The viruses are ubiquitous. The percent infection of the population varies from 30% to 85% and even 95%. In adults having a functional immune system, the infection has an uneventful course and exhibits unspecifical symptoms at most, such as exhaustion and slightly increased body temperature.
In immunodeficient adults afflicted with CMV infection, pulmonary diseases, choroiditis and gastro-intestinal diseases are prevailing. In AIDS patients, CMV infections are the major cause of death.
As the incidence of CMV infections increases with increasing age, a possible participation of cytomegaloviruses in arterial plaque formation is currently being discussed. The viruses are capable of damaging endothelial cells of the vascular walls.
Various substances are discussed for treatment against cytomegaloviruses.
The publication by J. Cinatl et al. (1994), Antiviral Research, Vol. 25: 73-77, describes desferrioxamine which forms iron chelates. In in-vitro experiments, this substance can be successfully used against Herpes simplex viruses, Varicella zoster viruses, Epstein-Barr viruses and human cytomegaloviruses. The mode of action of the substance is attributed to chelate formation with iron ions. Further, cellular ribonucleotide reductase is also believed to be inhibited. However, the results obtained as yet are partly contradictory in terms of theory. The substance exhibits low toxicity.
Foscarnet is an antiviral substance having a selective activity, as detected in cell cultures, against human viruses of the Herpes group, such as Herpes simplex, Varicella zoster, Epstein-Barr and cytomegaloviruses as well as hepatitis viruses. Its antiviral activity is based on an inhibition of viral enzymes, such as DNA polymerases and reverse transcriptases. On cytomegaloviruses, foscarnet has a virostatic effect, but the viruses cannot be eliminated (Lutz Schneider (1991), Pharmazeutische Zeitung, Vol. 136, No. 46, 33-36). An essential problem of cytomegaloviral infection is the necessity of a permanent, and sometimes life-long, treatment of the patients. A further disadvantage is that cytomegaloviruses have become more resistant against this substance recently (Stanat et al. (1991), Antimicrob. Agents, Chemother., Vol. 35, No. 11: 2191-2197, and Knox et al. (1991), Lancet, Vol. 337: 1292-1293).
Ganciclovir is described in the publication by Lutz Schneider (1990), Pharmazie, Vol. 135, No. 37, 2396-2400. Ganciclovir belongs to the nucleoside antimetabolites which are derived from 2'-deoxyguanosine. Instead of 2'-deoxyribose, it bears an acyclic side chain and is distinguished from aciclovir only by an additional hydroxymethyl group in the side chain. Ganciclovir has been approved for the treatment of life-threatening or eyesight-threatening cytomegaloviral infections in patients with acquired immunodeficiency or medicamentous immunosuppression, for example, after organ transplantations. Although ganciclovir is also effective with other human-pathogenic Herpes viruses (HSV 1 and 2, Varicella zoster and Epstein-Barr), its use in such infections is out of the question because of the high side-effect level. Ganciclovir leads to neutropenia, and mice under treatment with ganciclovir have been observed to develop tumors. A further disadvantage is that that cytomegaloviruses have become more resistant against this substance recently (Stanat et al. (1991), Lancet, Vol. 337: 1292-1293).
WO 94/22438 (DINU, date of application: Dec. 29, 1993) describes diethylenetriaminepentaacetic acid for the treatment of Herpes simplex, Varicella zoster, encephalomyelitis, polyradiculoneuritis, multiple sclerosis, but not of cytomegaloviruses. Immunosuppressants, such as cyclosporin A or tacrolimus, are successfully employed in organ transplantations in order to avoid or mitigate rejection reactions. Of course, a drawback is the susceptibility of the treated patients for severe complications caused by viral and bacterial infections. In particular, in this connection, infection with cytomegaloviruses may be mentioned.